The proton pump, located in the apical membrane of the parietal cell, is responsible for the secretion of acid in the stomach when it is stimulated by the enzyme adenosine triphosphate (H+, K+)-ATPase. Proton pump inhibitors are a class of anti-secretory compounds used in the management of gastrointestinal disorders. They suppress gastric acid secretion by the specific inhibition of the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell.
A family of substituted benzimidazoles have been developed as specific proton pump inhibitors. Two of these compounds, omeprazole and lansoprazole, are used clinically in the United States. Structurally they contain a sulfinyl group bridging between substituted benzimidazole and pyridine rings. At a neutral pH, omeprazole and lansoprazole are chemically stable, are weak bases, are lipid-soluble, and do not show any inhibitory activity. Once these compounds reach the parietal cells and diffuse into the secretory canaliculi, they become protonated. The protonated compounds rearrange to form sulfenic acid and then a sulfenamide. The latter interacts covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane spanning (H+, K+)-ATPase. Inhibition occurs when two molecules of the inhibitor are bound per molecule of the enzyme. The specificity of these proton pump inhibitors arises from the selective distribution of the (H+, K+)-ATPase, the acid-catalyzed rearrangement of the compounds to generate the active inhibitor, and the trapping of the protonated compound and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme.
Omeprazole and lansoprazole are typically administered orally as delay-release capsules. The compounds are stable at a neutral pH, but are destroyed by gastric acid. Therefore, if the integrity of the gelatin-coated capsule is destroyed in any way and the patient swallows the enteric-coated grains, the neutral pH in the mouth and the esophagus will break down the microencapsulation, and the compounds will be degraded by the gastric acid in the stomach. The delay release capsules, when appropriately taken, release the omeprazole and lansoprazole after the granules leave the stomach.
Despite their good anti-secretory properties, proton pump inhibitors are not unanimously recognized as gastroprotective agents. In addition, there is a high relapse rate associated with treating gastrointestinal disorders with proton pump inhibitors as they do not eliminate Helicobacter pylori (Campylobacter pylori), the bacteria responsible for peptic ulcer disease, gastric lymphoma and adenocarcinoma. U.S. Pat. Nos. 5,599,794 and 5,629,305 describe the administration of proton pump inhibitors in combination with acid-degradable antibacterial compounds for the treatment of infections caused by Helicobacter pylori. 
A variety of adverse reactions have been ascribed to proton pump inhibitors, such as omeprazole and lansoprazole, reflecting, in part, the very large number of patients who have been treated with these drugs. The incidence of adverse reactions is low, and the adverse reactions are generally minor. Due to the profound reduction in gastric acidity, there tends to be an increased secretion of gastrin. Hence, patients who take therapeutic doses of omeprazole and lansoprazole have modest hypergastrinemia. Prolonged administration of high doses of the drugs can cause hyperplasia of oxyntic mucosal cells.
The most common side effects of proton pump inhibitors, such as omeprazole and lansoprazole, are nausea, diarrhea, abdominal colic, and central nervous system effects such as headaches and dizziness. Occasionally skin rashes and transient elevations of plasma activities of hepatic aminotransferase have been reported. The drugs can also result in bacterial overgrowth in the gastrointestinal tract and the development of nosocomial pneumonia.
There is a need in the art for proton pump inhibitors that have improved gastroprotective properties, decrease the recurrence of ulcers, facilitate ulcer healing and that can be used at low dosages. The present invention is directed to these, as well as other, important ends.